Elevated glucose increases tumor necrosis factor‐α induced endothelial cell death via fibroblast growth factor‐2 release

Abstract

Diabetic vasculopathies are accompanied by elevated glucose and tumor necrosis factor‐α (TNFα). Yet the effect of TNFα on endothelial cell (EC) function in a high glucose environment has not been measured. We examined TNFα‐induced EC death under normal and elevated glucose conditions. Upon TNFα stimulation, EC cultured in 30 mM glucose had twice the apoptosis rate of cells cultured in 5 mM glucose (p < .01). Both high glucose culture and TNFα stimulation induced EC release of fibroblast growth factor‐2 (FGF2), an angiogenic growth factor that usually protects cells from death. Surprisingly, TNFα‐induced cell death increased linearly with FGF2 exposure, with a maximal effect when FGF2 was added 18 hours prior to TNFα stimulation. This timing correlated with cell entry into S phase. Indeed, the increase in TNFα‐induced cell death in high glucose was negated with a neutralizing FGF2 antibody or by preventing cell cycle progression through S phase. These data suggest that the elevated glucose and TNFα environment in diabetes compound to detrimentally affect ECs. Cells chronically stimulated with TNFα may respond in an alternate manner to growth factors such as FGF2. This deregulation of vascular homeostasis may contribute to diabetic vascular disease.